Obesity and type 2 diabetes are the most prevalent and serious of the metabolic disorders. A central regulator of insulin signaling implicated in the pathogenesis of the metabolic syndrome is the kinase JNK, a protein of the mitogen activated protein kinases (MAPK) family. In the past decade, JNK has been the subject of extensive research efforts from both the academic and private sectors for the development of potential small molecule inhibitors targeting its ATP binding site. However, because of the large number of ATP-binding proteins involved in complex cross-talk within signaling events (> 500 if considering only protein kinases), it is difficult to predict potential adverse events that might arise from inhibitors that directly target the ATP site of JNK, and major investigations in this area are ongoing. JNK activity is dependant on its interaction with a scaffolding protein named JIP1 (JNK-interacting protein 1). Recent studies have identified a minimal peptide region of JIP1 that inhibits JNK activity in vitro toward recombinant c-jun, Elk, and ATF2 with a remarkable selectivity. Further in vivo studies with a cell-permeable JIP1 peptide showed that its administration in both genetically and dietary obese mice restored normoglycemia but did not cause hypoglycemia in lean mice. These observations strongly support our idea that the interaction of JNK with JIP1 offers a valid alternative target for JNK inhibition. With the long term goal of advancing novel therapies against diabetes, we propose to use a combination of medicinal chemistry, NMR- and structure-based design to derive non-peptide allosteric JNK inhibitors targeting its JIP1 docking site and to test the developed compounds in cell and eventually in vivo models of diabetes. Relevance: Obesity is a chronic metabolic disorder that increases the likelihood of deadly metabolic diseases such as type 2 diabetes and various cardiovascular disorders and cause 280,000 to 325,000 deaths per year in the United States. Currently available drugs have rather limited efficacy as well as safety and/or tolerability concerns. Therefore, the development of novel, safe and highly efficacious treatments is becoming more of an imperative as metabolic disorders reach epidemic proportions. By exploring novel routes for the inhibition of a key modulator of the metabolic disorder, the protein target JNK, we hope to derive new agents to advance novel therapies against obesity and diabetes. [unreadable] [unreadable]